1. Background of Paclitaxel and Docetaxel
Taxanes, in particular, the two currently available drugs, Paclitaxel and Docetaxel, are potent antineoplastic agents. Taxanes are derived naturally or semi-synthetically from the bark or needles of certain yews. Paclitaxel was discovered in the late 1970s, and was found to be an effective antineoplastic agent with a mechanism of action different from existing chemotherapeutic agents.
In particular, Paclitaxel, Docetaxel and other taxanes exert cytotoxic effects by enhancing the polymerization of tubulin, which is an essential protein in the formation of spindle microtubules. The result is the formation of very stable, nonfunctional tubules, which inhibits cell replication and leads to neoplasm cell death. Taxanes are recognized as effective agents in the treatment of many solid tumors which are refractory to other antineoplastic agents.
Paclitaxel has a complex structure and is shown below as Formula I: ##STR1##
Paclitaxel is very poorly water soluble (less than 10 .mu.g/mL), and as a result, cannot be practically formulated with water for IV administration. Currently, Paclitaxel is formulated for IV administration to patients with cancer in a solution with polyoxyethylated castor oil (Polyoxyl 35 or Cremaphor.RTM.) as the primary solvent. High concentrations of ethanol are employed as co-solvents. One of the major difficulties in the administration of Paclitaxel is the occurrence of hypersensitivity reactions. These reactions, which include severe skin rashes, hives, flushing, dyspnea, tachycardia, and others, may be attributed at least in part to the high concentrations of alcohol and polyoxyl 35 used as solvents in the formulation.
Docetaxel is an analogue of Paclitaxel, and was recently approved for administration to patients with cancer by the United States Food & Drug Administration. Docetaxel has the following structure: ##STR2##
Like Paclitaxel, Docetaxel is very poorly soluble in water. The current most preferred solvent used to dissolve Docetaxel is polysorbate 80 (Tween 80). Like Polyoxyl 35, polysorbate often causes hypersensitivity reactions in patients. Further, polysorbate cannot be used with PVC delivery apparatus, because of its tendency to leech diethylhexyl phthalate, which is highly toxic.
Due to the relatively high viscosity of Cremaphor, co-solvents must be employed to allow for intravenous infusion of the formulation to the patient. Some commonly employed co-solvents include various lower alcohols, vegetable and other oils, and combinations of other organic and inorganic solvents. Other pharmaceutical excipients are also employed in making formulations of these drugs. Currently, only intravenous formulations of paclitaxel or docetaxel are available for administration to patients.
2. N-Methylpyrrolidone
N-methylpyrrolidin-2-one, also referred to as N-methylpyrrolidone, 1-methyl-2-pyrrolidone, NMP, and other like names, is a common industrial solvent. NMP has also been used in pharmaceutical formulations as an excipient to enhance the skin penetration of topically applied agents. NMP is a slow evaporating, highly polar, aprotic, general purpose solvent which is fully miscible with water and most organic solvents. The many uses of NMP are catalogued in the BASF brochure entitled N-Methylpyrrolidone (NMP), attached to the Information Disclosure Sheet (IDS). NMP has also been used in the preparation of pharmaceutical compounds as a solvent for various pharmaceuticals, namely Etoposide, Tetracycline, Doxycycline, Teniposide, Chlortetracycline, Camptothecins and other poorly water soluble pharmaceutical compounds. Prior patents regarding the use of NMP as such are identified in and attached to the Information Disclosure Sheet.